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Shaping Medicinal Chemistry for the New Decade

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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (31 July 2023) | Viewed by 18464

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Special Issue Editors

Prof. Dr. Diego Muñoz-Torrero

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Guest Editor

Laboratory of Medicinal Chemistry, Faculty of Pharmacy and Food Sciences, Institute of Biomedicine (IBUB), University of Barcelona, Avenue Joan XXIII, 27-31, E-08028 Barcelona, Spain
Interests: multitarget anti-Alzheimer agents; hybrid compounds; cholinesterase inhibitors; amyloid anti-aggregating compounds; BACE-1 inhibitors; antiprotozoan compounds
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Prof. Dr. Rino Ragno

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Rome Center for Molecular Design, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma, P. le A. Moro 5, 00185 Roma, Italy
Interests: medicinal chemistry; computational chemistry; 3D-QSAR; machine learning; drug design; extraction of natural compounds; essential oil
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Medicinal chemistry must be continuously shaped to confront changing therapeutic challenges, to adapt to emerging novel drug modalities, and to take advantage of new technologies with high potential to speed up drug discovery.

This Special Issue is related to the Third Molecules Medicinal Chemistry Symposium—Shaping Medicinal Chemistry for the New Decade (MMCS2022), which will be held in Rome (Italy) on July 27–29, 2022. At the Symposium, current challenges in the drug discovery field will be discussed while reporting novel and revisited drug discovery approaches against particularly challenging diseases, and medicinal chemistry stories about recently implemented projects in target and hit identification, hit-to-lead optimization, tuning of physicochemical and pharmacokinetic properties, preclinical and clinical development, etc.

Participants of the Symposium and all researchers working in the field are cordially invited to contribute original research articles, short communications, or reviews to this Special Issue of Molecules, reporting on recent innovative medicinal-chemistry projects, particularly (but not exclusively) regarding the design and development of novel drug candidates against drug-resistant microorganisms and SARS-CoV-2, different modalities of targeting protein degradation with therapeutic purposes, the use of machine learning in drug design, the use of natural products in drug discovery, and the rational design and profiling of multitarget agents to tackle multifactorial diseases. Participants of this conference are encouraged to contribute with a full manuscript to our Special Issue related to the conference in the journal Molecules. The conference participants will be granted a 30% discount on the publishing fees. For planned manuscripts, a title and short abstract (about 100 words) should be sent to the Editorial Office for announcement on this website.

Dr. Diego Muñoz-Torrero
Dr. Rino Ragno
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

drug discovery
drug design
drug synthesis
SARS-CoV-2
anti-infective agents
targeted protein degraders
multitarget drugs
machine learning
natural products
novel drugs

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Published Papers (8 papers)

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Research

18 pages, 8470 KiB

Open AccessArticle

Selenium Protects ARPE-19 and ACBRI 181 Cells against High Glucose-Induced Oxidative Stress

by Handan Bardak, Abdülhadi Cihangir Uğuz, Yavuz Bardak, Javier Rocha-Pimienta, Jonathan Delgado-Adámez and Javier Espino

Molecules 2023, 28(16), 5961; https://doi.org/10.3390/molecules28165961 - 9 Aug 2023

Cited by 3 | Viewed by 1610

Abstract

Diabetic retinopathy (DR), a complication of diabetes mellitus (DM), can cause severe visual loss. The retinal pigment epithelium (RPE) plays a crucial role in retinal physiology but is vulnerable to oxidative damage. We investigated the protective effects of selenium (Se) on retinal pigment epithelium (ARPE-19) and primary human retinal microvascular endothelial (ACBRI 181) cells against high glucose (HG)-induced oxidative stress and apoptotic cascade. To achieve this objective, we utilized varying concentrations of D-glucose (ranging from 5 to 80 mM) to induce the HG model. HG-induced oxidative stress in ARPE-19 and ACBRI 181 cells and the apoptotic cascade were evaluated by determining Ca²⁺ overload, mitochondrial membrane depolarization, caspase-3/-9 activation, intracellular reactive oxygen species (ROS), lipid peroxidation (LP), glutathione (GSH), glutathione peroxidase (GSH-Px), vascular endothelial growth factor (VEGF) and apoptosis levels. A cell viability assay utilizing MTT was conducted to ascertain the optimal concentration of Se to be employed. The quantification of MTT, ROS, VEGF levels, and caspase-3 and -9 activation was accomplished using a plate reader. To quantitatively assess LP and GSH levels, GSH-Px activities were utilized by spectrophotometer and apoptosis, mitochondrial membrane depolarization, and the release of Ca²⁺ from intracellular stores were evaluated by spectrofluorometer. Our investigation revealed a significant augmentation in oxidative stress induced by HG, leading to cellular damage through modulation of mitochondrial membrane potential, ROS levels, and intracellular Ca²⁺ release. Incubation with Se resulted in a notable reduction in ROS production induced by HG, as well as a reduction in apoptosis and the activation of caspase-3 and -9. Additionally, Se incubation led to decreased levels of VEGF and LP while concurrently increasing levels of GSH and GSH-Px. The findings from this study strongly suggest that Se exerts a protective effect on ARPE-19 and ACBRI 181 cells against HG-induced oxidative stress and apoptosis. This protective mechanism is partially mediated through the intracellular Ca²⁺ signaling pathway. Full article

(This article belongs to the Special Issue Shaping Medicinal Chemistry for the New Decade)

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22 pages, 1407 KiB

Open AccessArticle

Synthesis and Biological Evaluation of New Quinoline and Anthranilic Acid Derivatives as Potential Quorum Sensing Inhibitors

by Ivana Perković, Tanja Poljak, Kirsi Savijoki, Pekka Varmanen, Gordana Maravić-Vlahoviček, Maja Beus, Anja Kučević, Ivan Džajić and Zrinka Rajić

Molecules 2023, 28(15), 5866; https://doi.org/10.3390/molecules28155866 - 3 Aug 2023

Cited by 4 | Viewed by 2662

Abstract

Inhibiting quorum sensing (QS), a central communication system, is a promising strategy to combat bacterial pathogens without antibiotics. Here, we designed novel hybrid compounds targeting the PQS (Pseudomonas quinolone signal)-dependent quorum sensing (QS) of Pseudomonas aeruginosa that is one of the multidrug-resistant and highly virulent pathogens with urgent need of new antibacterial strategies. We synthesized 12 compounds using standard procedures to combine halogen-substituted anthranilic acids with 4-(2-aminoethyl/4-aminobuthyl)amino-7-chloroquinoline, linked via 1,3,4-oxadiazole. Their antibiofilm activities were first pre-screened using Gram-negative Chromobacterium violaceum-based reporter, which identified compounds 15–19 and 23 with the highest anti-QS and minimal bactericidal effects in a single experiment. These five compounds were then evaluated against P. aeruginosa PAO1 to assess their ability to prevent biofilm formation, eradicate pre-formed biofilms, and inhibit virulence using pyocyanin as a representative marker. Compound 15 displayed the most potent antibiofilm effect, reducing biofilm formation by nearly 50% and pre-formed biofilm masses by 25%. On the other hand, compound 23 exhibited the most significant antivirulence effect, reducing pyocyanin synthesis by over 70%. Thus, our study highlights the potential of 1,3,4-oxadiazoles 15 and 23 as promising scaffolds to combat P. aeruginosa. Additionally, interactive QS systems should be considered to achieve maximal anti-QS activity against this clinically relevant species. Full article

(This article belongs to the Special Issue Shaping Medicinal Chemistry for the New Decade)

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20 pages, 2770 KiB

Open AccessArticle

Biological Evaluation of Triorganotin Derivatives as Potential Anticancer Agents

by Valeria Stefanizzi, Antonella Minutolo, Elena Valletta, Martina Carlini, Franca M. Cordero, Anna Ranzenigo, Salvatore Pasquale Prete, Daniel Oscar Cicero, Erica Pitti, Greta Petrella, Claudia Matteucci, Francesca Marino-Merlo, Antonio Mastino and Beatrice Macchi

Molecules 2023, 28(9), 3856; https://doi.org/10.3390/molecules28093856 - 2 May 2023

Cited by 2 | Viewed by 1826

Abstract

Metal-derived platinum complexes are widely used to treat solid tumors. However, systemic toxicity and tumor resistance to these drugs encourage further research into similarly effective compounds. Among others, organotin compounds have been shown to inhibit cell growth and induce cell death and autophagy. Nevertheless, the impact of the ligand structure and mechanisms involved in the toxicity of organotin compounds have not been clarified. In the present study, the biological activities of commercially available bis(tributyltin) oxide and tributyltin chloride, in comparison to those of specially synthesized tributyltin trifluoroacetate (TBT-OCOCF₃) and of cisplatin, were assessed using cells with different levels of tumorigenicity. The results show that tributyltins were more cytotoxic than cisplatin in all the tested cell lines. NMR revealed that this was not related to the interaction with DNA but to the inhibition of glucose uptake into the cells. Moreover, highly tumorigenic cells were less susceptible than nontumorigenic cells to the nonunique pattern of death induced by TBT-OCOCF₃. Nevertheless, tumorigenic cells became sensitive when cotreated with wortmannin and TBT-OCOCF₃, although no concomitant induction of autophagy by the compound was detected. Thus, TBT-OCOCF₃ might be the prototype of a family of potential anticancer agents. Full article

(This article belongs to the Special Issue Shaping Medicinal Chemistry for the New Decade)

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10 pages, 1452 KiB

Open AccessArticle

Antimalarial Activity of Tri- and Tetra-Substituted Anilino Pyrazoles

by Matteo Lusardi, Nicoletta Basilico, Chiara Rotolo, Silvia Parapini and Andrea Spallarossa

Molecules 2023, 28(4), 1712; https://doi.org/10.3390/molecules28041712 - 10 Feb 2023

Cited by 3 | Viewed by 1869

Abstract

Pyrazole core represents a privilege scaffold in medicinal chemistry; a number of pyrazole compounds are endowed with various pharmacological activities in different therapeutic areas including antimalarial treatment. Supported by this evidence, a series of 5-anilino-3-(hetero)arylpyrazoles were evaluated for their antiplasmodial activity in in vitro assays. The compounds were synthesized according to regioselective and versatile protocols that combine active methylene reagents, aryl isothiocyanates and (substituted)hydrazines. The considered derivatives 2 allowed the definition of consistent structure–activity relationships and compounds 2b,e,k,l were identified as the most interesting derivatives of the series showing micromolar IC₅₀ values against chloroquine-sensitive and chloroquine-resistant Plasmodium strains. Additionally, the most active anilino-pyrazoles did not show any cytotoxicity against tumor and normal cells and were predicted to have favorable drug-like and pharmacokinetic properties. Full article

(This article belongs to the Special Issue Shaping Medicinal Chemistry for the New Decade)

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19 pages, 1131 KiB

Open AccessArticle

Molecular Toxicity Virtual Screening Applying a Quantized Computational SNN-Based Framework

by Mauro Nascimben and Lia Rimondini

Molecules 2023, 28(3), 1342; https://doi.org/10.3390/molecules28031342 - 31 Jan 2023

Cited by 2 | Viewed by 2199

Abstract

Spiking neural networks are biologically inspired machine learning algorithms attracting researchers’ attention for their applicability to alternative energy-efficient hardware other than traditional computers. In the current work, spiking neural networks have been tested in a quantitative structure–activity analysis targeting the toxicity of molecules. Multiple public-domain databases of compounds have been evaluated with spiking neural networks, achieving accuracies compatible with high-quality frameworks presented in the previous literature. The numerical experiments also included an analysis of hyperparameters and tested the spiking neural networks on molecular fingerprints of different lengths. Proposing alternatives to traditional software and hardware for time- and resource-consuming tasks, such as those found in chemoinformatics, may open the door to new research and improvements in the field. Full article

(This article belongs to the Special Issue Shaping Medicinal Chemistry for the New Decade)

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21 pages, 1871 KiB

Open AccessArticle

3-(Adenosylthio)benzoic Acid Derivatives as SARS-CoV-2 Nsp14 Methyltransferase Inhibitors

by Olga Bobileva, Raitis Bobrovs, Evelina Elva Sirma, Iveta Kanepe, Anna L. Bula, Liene Patetko, Anna Ramata-Stunda, Solveiga Grinberga, Aigars Jirgensons and Kristaps Jaudzems

Molecules 2023, 28(2), 768; https://doi.org/10.3390/molecules28020768 - 12 Jan 2023

Cited by 15 | Viewed by 2551

Abstract

SARS-CoV-2 nsp14 guanine-N7-methyltransferase plays an important role in the viral RNA translation process by catalyzing the transfer of a methyl group from S-adenosyl-methionine (SAM) to viral mRNA cap. We report a structure-guided design and synthesis of 3-(adenosylthio)benzoic acid derivatives as nsp14 methyltransferase inhibitors resulting in compound 5p with subnanomolar inhibitory activity and improved cell membrane permeability in comparison with the parent inhibitor. Compound 5p acts as a bisubstrate inhibitor targeting both SAM and mRNA-binding pockets of nsp14. While the selectivity of 3-(adenosylthio)benzoic acid derivatives against human glycine N-methyltransferase was not improved, the discovery of phenyl-substituted analogs 5p,t may contribute to further development of SARS-CoV-2 nsp14 bisubstrate inhibitors. Full article

(This article belongs to the Special Issue Shaping Medicinal Chemistry for the New Decade)

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21 pages, 6068 KiB

Open AccessArticle

New N4-Donor Ligands as Supramolecular Guests for DNA and RNA: Synthesis, Structural Characterization, In Silico, Spectrophotometric and Antimicrobial Studies

by Ernest Ewert, Izabela Pospieszna-Markiewicz, Martyna Szymańska, Adrianna Kurkiewicz, Agnieszka Belter, Maciej Kubicki, Violetta Patroniak, Marta A. Fik-Jaskółka and Giovanni N. Roviello

Molecules 2023, 28(1), 400; https://doi.org/10.3390/molecules28010400 - 3 Jan 2023

Cited by 3 | Viewed by 2562

Abstract

The present work reports the synthesis of new N4-donor compounds carrying p-xylyl spacers in their structure. Different Schiff base aliphatic N-donors were obtained synthetically and subsequently evaluated for their ability to interact with two models of nucleic acids: calf-thymus DNA (CT-DNA) and the RNA from yeast Saccharomyces cerevisiae (herein simply indicated as RNA). In more detail, by condensing p-xylylenediamine and a series of aldehydes, we obtained the following Schiff base ligands: 2-thiazolecarboxaldehyde (L1), pyridine-2-carboxaldehyde (L2), 5-methylisoxazole-3-carboxaldehyde (L3), 1-methyl-2-imidazolecarboxaldehyde (L4), and quinoline-2-carboxaldehyde (L5). The structural characterisation of the ligands L1-L5 (X-ray, ¹H NMR, ¹³C NMR, elemental analysis) and of the coordination polymers {[CuL1]PF₆}_n (herein referred to as Polymer1) and {[AgL1]BF₄}_n, (herein referred to as Polymer2, X-ray, ¹H NMR, ESI-MS) is herein described in detail. The single crystal X-ray structures of complexes Polymer1 and Polymer2 were also investigated, leading to the description of one-dimensional coordination polymers. The spectroscopic and in silico evaluation of the most promising compounds as DNA and RNA binders, as well as the study of the influence of the 1D supramolecular polymers Polymer1 and Polymer2 on the proliferation of Escherichia coli bacteria, were performed in view of their nucleic acid-modulating and antimicrobial applications. Spectroscopic measurements (UV–Vis) combined with molecular docking calculations suggest that the thiazolecarboxaldehyde derivative L1 is able to bind CT-DNA with a mechanism different from intercalation involving the thiazole ring in the molecular recognition and shows a binding affinity with DNA higher than RNA. Finally, Polymer2 was shown to slow down the proliferation of bacteria much more effectively than the free Ag(I) salt. Full article

(This article belongs to the Special Issue Shaping Medicinal Chemistry for the New Decade)

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10 pages, 2028 KiB

Open AccessArticle

Insights into Antimalarial Activity of N-Phenyl-Substituted Cinnamanilides

by Jiri Kos, Gilles Degotte, Dominika Pindjakova, Tomas Strharsky, Timotej Jankech, Tomas Gonec, Pierre Francotte, Michel Frederich and Josef Jampilek

Molecules 2022, 27(22), 7799; https://doi.org/10.3390/molecules27227799 - 12 Nov 2022

Cited by 3 | Viewed by 1764

Abstract

Due to the urgent need of innovation in the antimalarial therapeutic arsenal, a series of thirty-seven ring-substituted N-arylcinnamanilides prepared by microwave-assisted synthesis were subjected to primary screening against the chloroquine-sensitive strain of P. falciparum 3D7/MRA-102. The lipophilicity of all compounds was experimentally determined as the logarithm of the capacity factor k, and these data were subsequently used in the discussion of structure-activity relationships. Among the screened compounds, fourteen derivatives exhibited IC₅₀ from 0.58 to 31 µM, whereas (2E)-N-(4-bromo-2-chlorophenyl)-3-phenylprop-2-enamide (24) was the most effective agent (IC₅₀ = 0.58 µM). In addition, (2E)-N-[2,6-dibromo-4-(trifluoromethyl)- phenyl]-3-phenylprop-2-enamide (36), (2E)-N-[4-nitro-3-(trifluoromethyl)phenyl]-3-phenylprop- 2-enamide (18), (2E)-N-(2-bromo-5-fluorophenyl)-3-phenylprop-2-enamide (23), and (2E)-3-phenyl-N-(3,4,5-trichlorophenyl)prop-2-enamide (33) demonstrated efficacy in the IC₅₀ range from 2.0 to 4.3 µM, comparable to the clinically used standard chloroquine. The results of a cell viability screening performed using THP1-Blue™ NF-κB cells showed that none of these highly active compounds displayed any significant cytotoxic effect up to 20 μM, which makes them promising Plasmodium selective substances for further investigations. Full article

(This article belongs to the Special Issue Shaping Medicinal Chemistry for the New Decade)

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